Purpose. The international 1000 Genomes Project
is designed to produce a new high-resolution resource on human genetic variation
to support genome-wide association studies and other studies of human disease
and biology. The primary source of data will be light sequencing of the
genomes of about 1200-1500 anonymized individuals. These data should be
sufficient to find most DNA sequence variants in the human population that have
a frequency of 1% or more. Several large-scale sequencing centers,
including three funded by NHGRI, are involved in this international
effort. Currently pilot projects are underway to assess the sequencing
platforms and provide data that will be used to design the full-scale
project. By the end of 2008 the full-scale project should be underway; it
is expected to take about two years and produce about 20 Terabases of sequence
data. The Project regularly will release raw sequence data and data
derived from the sequence data, such as genotype calls for single-nucleotide
polymorphisms (SNPs) and structural variants, and their linkage disequilibrium
patterns. This FOA solicits proposals to characterize and analyze the
full dataset, such as for allele frequency distribution and signals of natural
selection, to produce additional data types, to evaluate the strategies used to
develop the dataset, and to develop the tools needed to work with the data and
apply them to other studies such as genome-wide association studies.

Mechanism of Support. This FOA will utilize the U01 cooperative agreement grant mechanism.

Funds Available and Anticipated Number
of Awards.The total
amount of funding that the NHGRI expects to award through this announcement is
up to $4 million for each of two years. It is anticipated that about 8-10
awards will be made.

Budget and Project Period.An
application submitted for this FOA may request a project period of up to two
years and direct costs of up to $300,000 per year.

Application Research Plan Component Length:The
page limit is 25 pages for Items 2-5 of the Research Plan.

Eligible Project
Directors/Principal Investigators (PDs/PIs). Individuals
with the skills, knowledge, and resources necessary to carry out the
proposed research are invited to work with their institution/organization
to develop an application for support. Individuals from underrepresented
racial and ethnic groups as well as individuals with disabilities are
always encouraged to apply for NIH support.

Number of Applications.Applicants
may submit more than one application, provided they are scientifically
distinct.

Resubmissions.Resubmission
applications are not permitted in response to this FOA.

Renewals.Renewal
applications are not permitted in response to this FOA.

In the last two years, genome-wide
association (GWA) studies have been successful in finding hundreds of variants
that are associated with diseases or other traits. These discoveries
became possible because of the availability of a large catalog of single
nucleotide polymorphisms (SNPs) across the human genome and the development of
dense genotyping microarrays. These arrays are based on data from the
International HapMap Project that show the pattern of variation across the
genome. The arrays allow genotyping to be done in case and control
samples at sufficient resolution to find regions of the genome that are
associated with particular diseases or other traits.

This approach can provide only a general
genomic location for the actual disease-causing or risk-elevating
variants. The arrays type only a fraction of the variants found in the
genome, because the HapMap data consist mostly of variants with a frequency of
at least 5%. However, many other variants, both SNP and structural, also
occur in any genomic region, and variants with lower frequencies also
contribute to disease risk. Thus the initial follow-up to a GWA study
finding that a region is associated with a disease or other trait is to try to
discover all the other, untyped, variants in the region. Even then,
it is usually not clear which genes and variants in the region causally
contribute to the disease risk, because generally many variants in a region are
statistically associated with each other. Thus, finding the full set of
variants in the region is necessary, but determining which variants and genes
cause the disease risk requires additional, functional studies to analyze their
potential roles.

The international 1000 Genomes Project
(www.1000genomes.org) is designed to support GWA studies by providing a public
resource of almost all genetic variants across the human genome with a
frequency of 1% or higher, and of genetic variants with even lower frequencies
in gene regions. When the 1000 Genomes resource is available,
investigators will not have to take the time and expense to follow up a GWA
study by sequencing the regions of interest; they will be able to look in a
public database and find an almost complete catalog of the variants in those
regions, including almost all of the ones that functionally cause the increased
disease risk.

The 1000 Genomes Project has developed
rapidly since its adoption at an international meeting in September of
2007. It will be the first large-scale project to use the next-generation
sequencing platforms for extensive human resequencing. The sequence data
for the Project will be generated at the NHGRI-funded centers at the Baylor
College of Medicine, the Broad Institute of MIT and Harvard, and Washington University in St. Louis, as well as centers at the Wellcome Trust Sanger Institute,
the Beijing Genomics Institute Shenzhen, the Max Planck Institute for Molecular
Genetics, Applied Biosystems, Illumina, and Roche.

The strategy initially proposed for the 1000
Genomes Project is to sequence the genomes of 1200-1500 individuals to a depth
of coverage of at least 4X (haploid equivalents) across the genome and 12X in
gene regions. To test the value of this approach and to address several
other issues related to the design of the full-scale effort, the Project has
begun with three pilot projects. Sequence data production for the pilot
projects started in January 2008 and should be finished early in 2009.
The data from these pilots will be analyzed, and the design for the full-scale
project will be developed by early 2009. Sequencing for the full-scale
project should start in the fall of 2008 and continue for about two years,
through about the end of 2010. The entire sequence dataset is anticipated
to be at least 20 Terabases, a massive amount of data.

The 1000 Genomes Project dataset has been
identified as a community resource, as described in the proceedings of the Meeting on Sharing Data from
Large-Scale Biological Research Projects
(http://www.wellcome.ac.uk/doc_wtd003208.html). The Project plans
to release the raw sequence data and many processed data types publicly,
quickly, and on a regular basis. The sequencing centers already send the
raw sequence reads regularly to the Project’s Data Coordination Center
(DCC), provided jointly by the European Bioinformatics Institute (EBI) and the National Center for Biotechnology Information (NCBI) of NIH, which quickly deposits them in
the public Short-Read Archive database.

Because the next-generation sequencing
platforms are in an early stage for production use, a number of analytical
methods are still being developed to use the raw sequence reads to produce the
derived data types that most users will need. Some of these methods, such
as generating data quality scores, will apply to many types of sequencing
projects. Others, such as combining data across samples, will be more
specific to the 1000 Genomes Project. Data-processing pipelines are
currently being developed that will allow the DCC to use the sequence reads to
provide several derived data types, such as read alignments, SNPs and
structural variants, and genotypes of individual samples, along with their quality
measures. When the Project has produced the full 1000 Genomes dataset,
many other types of analyses will be needed to characterize it and make it more
useful for the research community. The Project plans to release publicly
the software that will be used to produce the various data types and analyze
the dataset.

All of the data analysis activities for the
1000 Genomes Project are being coordinated through the Project’s
Production, Analysis, and Data Processing Groups, working with the DCC.
Some of the participating research groups have funding from NIH or elsewhere to
work on specific analyses. Other critical analysis work, however, is as
yet unfunded.

Objectives of
This Research Program

This FOA and its companion FOA (RFA-HG-09-001)
aim to address the analysis needs of the 1000 Genomes Project on two
timescales:

1. The companion FOA (RFA-HG-09-001 “1000 Genomes Project Data
Processing”) solicits proposals to perform the analyses needed to produce the 1000 Genomes
dataset. It calls for proposals to carry out the analysis work needed to
process the primary sequence data to produce the full derived Project dataset.

The companion FOA
solicits proposals to continue to develop, evaluate, and implement the methods
needed to produce the derived data types from the sequence data, monitor the
quality of the data, integrate the data types, develop the tools needed to work
with the data, and develop new processes as needed to produce the full derived
Project dataset.

Because of the timing
of the companion FOA, the initial software pipelines for the DCC to process the
data will already have been set up when the awards are made. The two-year
award period (July 2009 to June 2011) should allow for the development and
implementation of the processes needed to produce the several derived data
types on a regular basis. The sequencing is anticipated to be finished
before these awards end, so that the full derived dataset can be produced using
the entire set of Project sequence data.

2. This FOA
(RFA-HG-09-002 “1000 Genomes Project Dataset
Analysis”),
in contrast, solicits proposals to analyze the full Project dataset, after it
has been produced by work funded through the companion RFA-HG-09-001.
This RFA-HG-09-002 calls for proposals to carry out the analysis work needed to
maximize the value of the full 1000 Genomes Project dataset to the general
research community

This FOA solicits
proposals to characterize the dataset, provide additional derived data types,
perform global analyses on the data, and develop better tools for using the
dataset to study biomedical and biological research problems.

Because of the timing
of this FOA, awardees will start to work with the dataset in about April 2010,
before it is complete. This will allow them time to become familiar with
the data, develop the methods using subsets of the data, and then be ready to
analyze the full dataset when it becomes available, which is anticipated to be
roughly in early 2011. Awardees will then have about a year to perform
the analyses on the data. These awards are being made for only two years
because it will be important to provide these characterizations, analyses, and
tools rapidly so that the research community will be able to make full use of
the 1000 Genomes resource as soon as possible.

Research Scope

Applicants for this FOA should propose to (a)
develop the methods to characterize the full 1000 Genomes dataset; (b) develop
the methods to provide derived datasets based on the 1000 Genomes dataset; (c)
develop the methods to perform global analyses of the 1000 Genomes dataset; (d)
evaluate the strategies that were used to develop the 1000 Genomes dataset; or
(e) develop tools to allow the several 1000 Genomes data types to be used by
researchers. Since the 1000 Genomes dataset is expected to support many
types of studies, the proposed analyses should be broadly useful to the
research community. They should also propose to develop the software to
implement these methods, including documentation. Software developed by awardees
should be modular, so that it can work as a stand-alone package. When
possible, the software should use standard formats for data input and output,
to facilitate its use and incorporation into central pipelines. These
standard formats should be ones that the Project has already decided on, or, if
new standard formats are needed, ones that the awardees develop in close
collaboration with others in the Project Analysis Group and the DCC. The
DCC is responsible for incorporating any software into its pipelines.
Awardees will also be responsible for monitoring the Project data produced
using their methods, and making adjustments to the methods as needed to correct
problems or make improvements.

Although the DCC generally would be expected
to run these analyses, the awardee might do so based on the types of analyses
and the computing needs. If awardees run any analyses, they would
generate Project datasets. As part of developing the analysis methods,
awardees may also generate resource datasets that would be useful to others in
the Project or more broadly, such as simulated datasets, test datasets, or
annotated validation datasets. These datasets should be released publicly
at the time that they are used to develop or analyze the main Project dataset.

Examples of research topics for this FOA include, but are
not limited to, those listed
below:

1. Analyze genomic coverage.
Methods will need to be developed to provide the depth of sequence coverage
across the genome and in gene regions, and to assess how the depth affects the
data quality. The methods may incorporate random and systematic biases,
which will produce different types of errors.

2. Analyze the frequency distribution
of variants. A major goal of the Project is to find rare variants, so methods
will need to be developed to examine the frequency distributions of various
types of variants genome-wide and in gene regions.

3. Analyze haplotypes and the value of
combining data across samples. Combining data across samples is a major
analysis strategy of the Project for finding variants and inferring
haplotypes. Although haplotypes are expected to be produced as part
of the derived Project dataset, additional methods for analyzing the haplotypes
will need to be developed, and it will be important to assess how well this
strategy of combining data works.

4. Analyze special regions.
Regions such as HLA, which have extensive sequence diversity and structural
variation, will require the development of methods tailored to their
characteristics. Note that the goal remains to characterize the entire
1000 Genomes resource, not to study particular regions because of biological or
medical interest.

5. Analyze Imputed variants.
Another major goal of the Project is to impute variants so that GWA studies can
use those data for association analyses. Although imputed variants are
expected to be produced as part of the derived Project dataset, additional
methods for analyzing the imputed data will need to be developed, including
examining how well variants of different types and frequencies can be imputed
genome-wide and in gene regions.

6. Produce additional data types.
The derived Project dataset will have the basic data types needed by the
community, but genome-wide methods need to be developed to provide additional
useful data types from the sequence data, the initial derived data types, or
these data types in combination with additional data types. The
additional data types could include the sequence or sequence variability in
other species or expression data.

7. Compare populations. The
populations to be studied in the Project are expected to have some differences
in allele frequencies, the amount of variation, and LD patterns. Methods
need to be developed to compare populations, evaluate admixture, and assess the
value of the Project strategy of using sets of related populations to provide
additional information on rare alleles.

8. Look for signals of natural
selection. Methods need to be developed to study this large Project dataset,
with many individuals and several populations, for various types of signals of
natural selection.

9. Consider how the resource should be
improved. By the time the Project dataset is produced, several studies of
sequencing for follow-up to GWA studies should have been analyzed. It
will be useful to develop methods to assess how well the data from the 1000
Genomes Project meet the needs of this follow-up for finding almost all
variants in regions found to be associated with disease, and what additional
data will be needed.

10. Develop tools for accessible
analyses of the data for GWA and other studies. The Project will produce
a massive dataset; maximizing its value to the scientific community will
require the development of many tools to filter, visualize, and examine the
data.

As much as possible, these analyses should be
performed across the entire genome or in the entire set of gene regions, using
all the samples. This FOA will not support the use of 1000 Genomes data
for the analysis of the genetics of specific human diseases or other
phenotypes.

This funding opportunity
will use a cooperative agreement award mechanism. In
the cooperative agreement mechanism, the Project Director/Principal
Investigator (PD/PI) retains the primary responsibility and dominant role for
planning, directing, and executing the proposed project, with NIH staff being
substantially involved as a partner with the Principal Investigator, as
described under the Section VI. 2. Administrative
Requirements, "Cooperative Agreement Terms and Conditions of
Award".

Plans beyond the current funding opportunity are indefinite.

2. Funds Available

The total amount of funding that the NHGRI expects
to award through this announcement is up to $4 million for each of two
years.

It is anticipated
that about 8-10 awards will be made.

An application submitted for this FOA may request a
project period of up to two years and direct costs of up to $300,000 per
year.

Because the nature
and scope of the proposed research will vary from application to application,
it is anticipated that the size and duration of each award will also vary.
Although the financial plans of the IC(s) provide support for this program,
awards pursuant to this funding opportunity are contingent upon the
availability of funds and the receipt of a sufficient number of meritorious
applications.

Facilities and
administrative costs requested by consortium participants are not included in
the direct cost limitation, see NOT-OD-05-004.

Applications must be
prepared using the most current PHS 398 research grant application instructions
and forms. Applications must have a D&B Data Universal Numbering System
(DUNS) number as the universal identifier when applying for Federal grants or
cooperative agreements. The D&B number can be obtained by calling (866)
705-5711 or through the web site at http://www.dnb.com/us/.
The D&B number should be entered on line 11 of the face page of the PHS 398
form.

The title and number of this funding opportunity must be typed in item (box) 2 only of the face page of
the application form and the YES box must be checked.

Prospective
applicants are asked to submit a letter of intent that includes the following
information:

Descriptive title of proposed research

Name, address, and telephone number of
the Principal Investigator

Names of other key personnel

Participating institutions

Number and title of this funding
opportunity

Although a letter of
intent is not required, is not binding, and does not enter into the review of a
subsequent application, the information that it contains allows IC staff to
estimate the potential review workload and plan the review.

Applications must be
prepared using the forms found in the PHS 398 instructions for preparing a
research grant application. Submit a signed, typewritten original of the
application, including the checklist, and three signed photocopies in one package to:

Applications must be received on or before the
application receipt date) described above (Section
IV.3.A.). If an application is received after that date, the application
may be delayed in the review process or not reviewed. Upon receipt,
applications will be evaluated for completeness by the CSR and for responsiveness by the reviewing Institute Incomplete and/or non-responsive applications
will not be reviewed.

The NIH will not
accept any application in response to this funding opportunity that is
essentially the same as one currently pending initial review, unless the
applicant withdraws the pending application. However, when a previously
unfunded application, originally submitted as an investigator-initiated
application, is to be submitted in response to a funding opportunity, it is to
be prepared as a NEW application. That is, the application for the funding
opportunity must not include an Introduction describing the changes and
improvements made, and the text must not be marked to indicate the changes from
the previous unfunded version of the application.

All NIH awards are
subject to the terms and conditions, cost principles, and other considerations
described in the NIH Grants Policy Statement. The Grants Policy Statement can
be found at NIH Grants
Policy Statement.

Pre-award costs are allowable. A grantee may, at its
own risk and without NIH prior approval, incur obligations and expenditures to
cover costs up to 90 days before the beginning date of the initial budget
period of a new award if such costs: 1) are necessary to conduct the project,
and 2) would be allowable under the grant, if awarded, without NIH prior
approval. If specific expenditures would otherwise require prior approval, the
grantee must obtain NIH approval before incurring the cost. NIH prior approval
is required for any costs to be incurred more than 90 days before the beginning
date of the initial budget period of a new award.

The incurrence
of pre-award costs in anticipation of a competing or non-competing award
imposes no obligation on NIH either to make the award or to increase the amount
of the approved budget if an award is made for less than the amount anticipated
and is inadequate to cover the pre-award costs incurred. NIH expects the
grantee to be fully aware that pre-award costs result in borrowing against
future support and that such borrowing must not impair the grantee's ability to
accomplish the project objectives in the approved time frame or in any way
adversely affect the conduct of the project (see NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.)

6. Other Submission Requirements and Information

Applicants
should describe their expertise with analyses of 1000 Genomes data or similar
data. They should describe how the proposed analyses would coordinate
with analyses already being done by the Project. See www.1000genomes.org
for a list of analyses being done by the Project, and for any additional
information on this FOA.

Applicants should describe how they will develop the
analyses and the software to run the analyses. They should describe the
input and output data types and formats. They should explain how they
will transfer the software to the DCC and work with the DCC to implement the
analyses. Alternatively,
if applicants propose that the DCC should not run a particular analysis
centrally, they should justify why they or some other group should run that
analysis, and explain how they would transfer the
derived dataset to the DCC.

Applicants should describe any resource datasets (e.g.,
simulated data) that they would develop, and explain how they would disseminate
them.

Applicants should describe the computing resources that
are needed for the analyses and what resources they have available.

The Project has regular conference calls and
meetings. Applicants should request funds over the two years to attend
Project meetings once in the U.K., in May 2010 and May 2011 at the Cold Spring
Harbor Laboratory, and prior to the 2010 and 2011 meetings of the American
Society of Human Genetics.

Awardees must agree to the "Cooperative Agreement
Terms and Conditions of Award" in Section VI.2.A "Award
Administration Information".

Do
not use the Appendix to circumvent the page limitations of the Research Plan
component. An application that does not observe the required page limitations
may be delayed in the review process.

Resource Sharing
Plan(s)

NIH considers the sharing of unique research
resources developed through NIH-sponsored research an important means to
enhance the value of, and advance research. When resources have been developed
with NIH funds and the associated research findings published or provided to
NIH, it is important that they be made readily available for research purposes
to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing,
this must be explained in Resource Sharing section of the application. See http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.

NHGRI has identified the 1000 Genomes
Project as a community resource project. A primary objective of the 1000
Genomes Project is to maximize the public benefit of the data produced. NIH strongly endorses rapid release of genomic data and
software as a general practice. The 1000 Genomes
Project aims to release all Project data rapidly before publication. The
Project data produced by the sequencing centers and the data-processing
pipelines of the DCC are not supported by this FOA. This FOA supports the
development of the methods that will be used to produce the various data types
from the sequence reads or basic derived data types.

i. Methods and
datasets: As awardees develop methods and analyze 1000 Genomes data, they
may generate primary Project datasets, as well as secondary resource datasets
that would be of use to other researchers. Examples of such resource
datasets include simulated data, test datasets, and annotated validation
data. These datasets and descriptions of all the methods developed would
be useful to the research community when the methods are implemented in the
1000 Genomes production pipelines (generally by the DCC but possibly by other
groups). Applicants should describe the schedule for methods and resource
dataset sharing, the formats of the datasets, the documentation to be provided,
and the mode of data sharing (e.g., mailing a disk, posting on a web site, or
providing the data and methods descriptions to the DCC or other
database).

ii.
Software: Applications that propose to develop software must include a
dissemination plan, with appropriate timelines. There is no particular
prescribed license for software produced through awards supported through this
FOA, although open-source software sharing is strongly encouraged. NHGRI
has goals for software dissemination, and reviewers will be instructed to
evaluate the dissemination plan relative to these goals:

1. The software,
including the source code, should be freely available to the broad research
community.

2. The terms of
software availability should permit the commercialization of enhanced or
customized versions of the software, and incorporation of the software or
pieces of it into other software packages.

3. To preserve
utility to the community, the software should be transferable so that another
group could continue development if the original investigators were unwilling
or unable to do so.

4. The terms of
software availability should allow researchers to modify the source code and to
share modifications with other colleagues. An awardee should be
responsible for creating the original and subsequent “official”
versions of a piece of software, and should provide a plan to manage the
dissemination, adoption of improvements, or customizations of that software by
others. This plan should include a method to distribute other user's
contributions such as extensions, compatible modules, or plug-ins.

(b) Sharing Model Organisms:
Regardless of the amount requested, all applications where the development of
model organisms is anticipated are expectedto include a
description of a specific plan for sharing and distributing unique model
organisms and related resources, or state appropriate reasons why such sharing
is restricted or not possible. See Sharing
Model Organisms Policy, and NIH
Guide NOT-OD-04-042.

(c) Genome-Wide Association Studies (GWAS): Regardless
of the amount requested, applicants seeking funding for a genome-wide
association study are expected to provide a plan for submission of GWAS data to the NIH-designatedGWAS data repository, or provide an appropriate
explanation why submission to the repository is not possible. A
genome-wide association study is defined as any study of genetic variation
across the entire genome that is designed to identify genetic associations with
observable traits (such as blood pressure or weight) or the presence or absence
of a disease or condition. For further information see Policy for Sharing
of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH
Guide NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.

Section
V. Application Review Information

1. Criteria (Update: Enhanced review criteria have been issued for the evaluation of research applications received for potential FY2010 funding and thereafter - see NOT-OD-09-025).

Only the review
criteria described below will be considered in the review process.

2. Review and Selection Process

Applications that are complete and
responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review
group convened by NHGRI and in accordance with NIH
peer review procedures (http://grants1.nih.gov/grants/peer/),
using the review criteria stated below.

As part of the scientific peer
review, all applications will:

Undergo
a selection process in which only those applications deemed to have the
highest scientific and technical merit, generally the top half of
applications under review, will be discussed and assigned a priority
score.

Receive
a written critique.

Receive
a second level of review by the Advisory
Council for Human Genome Research.

The
following will be considered in making funding decisions:

Scientific
and technical merit of the proposed project as determined by peer review

Availability
of funds

Relevance
of the proposed project to program priorities

Importance
and general usefulness of the proposed analyses

Balance
among areas of analysis

Need
for support for the proposed analyses

Willingness
of the applicant to work cooperatively with researchers in the rest of the
1000 Genomes Project

Quality
of the plans to release datasets and share methods and software

The
goals of NIH supported research are to advance our understanding of biological
systems, to improve the control of disease, and to enhance health. In their
written critiques, reviewers will be asked to comment on each of the following
criteria in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals. Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application. Note that an application does not need to be
strong in all categories to be judged likely to have major scientific impact
and thus deserve a meritorious priority score. For example, an investigator may
propose to carry out important work that by its nature is not innovative but is
essential to move a field forward.

Significance: Does this study address an important problem? If the
aims of the application are achieved, how will scientific knowledge or clinical
practice be advanced? What will be the effect of these studies on the concepts,
methods, technologies, treatments, services, or preventative interventions that
drive this field?Will
the proposed analyses be useful for a large part of the community of users of
the dataset?

Approach: Are the conceptual or clinical framework, design,
methods, and analyses adequately developed, well integrated, well reasoned, and
appropriate to the aims of the project? Does the applicant acknowledge
potential problem areas and consider alternative tactics? If appropriate, are the approaches integrated with other analyses
for the Project? Are the plans for sharing the methods, software, and
any datasets adequate and appropriate for the Project?

Innovation: Is the project original and innovative? For example:
Does the project challenge existing paradigms or clinical practice; address an
innovative hypothesis or critical barrier to progress in the field? Does the
project develop or employ novel concepts, approaches,
methodologies, tools, or technologies for this area?Is
the level of innovation appropriate for the role of the proposed analyses in
the Project?

Investigators: Are the investigators appropriately trained and well suited
to carry out this work? Is the work proposed appropriate to the experience
level of the principal investigator and other researchers? Does the
investigative team bring complementary and integrated expertise to the project
(if applicable)?Do the investigators have
experience in working cooperatively with others and sharing data and methods in
a timely manner?

Environment: Does the scientific environment in which the work
will be done contribute to the probability of success? Do the proposed studies
benefit from unique features of the scientific environment, or subject
populations, or employ useful collaborative arrangements? Is there evidence of
institutional support?

2.A.
Additional Review Criteria:

In addition to the
above criteria, the following items will continue to be considered in the
determination of scientific merit and the rating:

Protection of Human Subjects from Research Risk: The involvement of human
subjects and protections from research risk relating to their participation in
the proposed research will be assessed (see the Research Plan section on Human
Subjects in the PHS 398 instructions).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to
include subjects from both genders, all racial and ethnic groups (and
subgroups), and children as appropriate for the scientific goals of the
research will be assessed. Plans for the recruitment and retention of subjects
will also be evaluated (see the Research Plan section on Human Subjects in the
PHS 398 instructions).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to
be used in the project, the five points described in the Vertebrate Animals
section of the Research Plan will be assessed.

Biohazards: If materials or procedures are proposed that are
potentially hazardous to research personnel and/or the environment, determine
if the proposed protection is adequate.

2.B. Additional Review
Considerations

Budget: The reasonableness of the
proposed budget and the requested period of support in relation to the proposed
research. The priority score should not be affected by the evaluation of the
budget.

2.C.
Resource Sharing Plan(s)

When relevant, reviewers will be instructed to comment
on the reasonableness of the following Resource Sharing Plans, or the rationale
for not sharing the following types of resources. However, reviewers will not
factor the proposed resource sharing plan(s) into the determination of
scientific merit or priority score, unless noted otherwise in the FOA. Program
staff within the IC will be responsible for monitoring the resource sharing.

All applications
must include a plan for sharing research data. All investigators
responding to this funding opportunity should include a description of how
methods, datasets, and software will be shared, or explain why data sharing is
not possible. However, rapid release of the methods, datasets, and
software would benefit the scientific user community because of the scope of
this community resource project.

Data Sharing
Plans: For this FOA, the reasonableness of the
plans for sharing methods, datasets, and software or the rationale for not
sharing them will be assessed by the reviewers. Reviewers will factor the
proposed data sharing plan into the determination of scientific merit and the
priority score. The adequacy of the sharing plans will be considered by
Program staff of the funding organization when making recommendations about
funding applications. Program staff may negotiate modifications of the
sharing plans with the awardee before recommending funding of an
application. The final version of the sharing plans will become a
condition of the award of the grant. The funding organization will be
responsible for monitoring the data sharing policy.

3. Anticipated Announcement and Award
Dates

It
is anticipated that applications will be reviewed late in 2009 and that awards
will be made in the spring of 2010.

Section
VI. Award Administration Information

1. Award Notices

After the peer review
of the application is completed, the PD/PI will be able to access his or her
Summary Statement (written critique) via the eRA Commons.

A
formal notification in the form of a Notice of Award (NoA) will be
provided to the applicant organization. The NoA signed by the grants management
officer is the authorizing document. Once all administrative and programmatic
issues have been resolved, the NoA will be generated via email notification
from the awarding component to the grantee business official (designated in
item 12 on the Application Face Page). If a grantee is not email enabled, a
hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an
authorization to begin performance. Any costs incurred before receipt of the
NoA are at the recipient's risk. These costs may be reimbursed only to the
extent considered allowable pre-award costs. See Also Section
IV.5. Funding Restrictions.

2. Administrative and National
Policy Requirements

Samples: The
samples to be used by the 1000 Genomes Project will have been decided on by the
Project. They include many samples from both sexes, most racial groups,
and several ethnic groups, as well as some children (although subject age is
not scientifically relevant for this study). Awardees will analyze
publicly available data from anonymized subjects, so the research is not
considered to be on human subjects.

Intellectual property: A primary objective of the 1000 Genomes Project is to
maximize the public benefit of the data produced. Accordingly, awardeesshould manage intellectual property (IP) and data in a way that achieves
this goal. For the 1000 Genomes Project, awardees are expected to contribute
to the generation of a large collection of data that will serve as a foundation
for the scientific community to develop future diagnostics, therapeutics, and
other medical applications. To achieve the objective of producing and broadly
sharing the resources generated by the 1000 Genomes Project, applicants should
develop a comprehensive IP and data management strategy that is consistent with
the NIH Research Tools Policy (http://ott.od.nih.gov/policy/research_tool.html).
Examples that applicants may wish to consider include the recommendations cited
in NIH’s Best Practices for the Licensing of Genomic Inventions (http://www.ott.nih.gov/policy/genomic_invention.html). Program staff may negotiate modifications of
the IP management plan with the awardee before recommending funding of an
application. The final version of the IP management plan will become part
of the Terms and Conditions of the award.

The
following Terms and Conditions will be incorporated into the award statement
and will be provided to the Principal Investigator as well as to the
appropriate institutional official, at the time of award.

2.A.
Cooperative Agreement Terms and Conditions of Award

The following special
terms of award are in addition to, and not in lieu of, otherwise applicable OMB
administrative guidelines, HHS grant administration regulations at 45 CFR Parts
74 and 92 (Part 92 is applicable when State and local Governments are eligible
to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and
funding instrument used for this program will be the cooperative agreement an
"assistance" mechanism (rather than an "acquisition"
mechanism), in which substantial NIH programmatic involvement with the awardees
is anticipated during the performance of the activities. Under the cooperative
agreement, the NIH purpose is to support and stimulate the recipients'
activities by involvement in and otherwise working jointly with the award
recipients in a partnership role; it is not to assume direction, prime
responsibility, or a dominant role in the activities. Consistent with this
concept, the dominant role and prime responsibility resides with the awardees
for the project as a whole, although specific tasks and activities may be
shared among the awardees and the NIH as defined below.

2.
A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator will have the primary
responsibility for defining the details for the project within the
guidelines of RFA-HG-09-002 and for performing the scientific activities.
The P.I. will agree to accept close coordination, cooperation, and
participation of NIH staff in those aspects of scientific and technical
management of the project as described under "NIH Program Staff
Responsibilities".

Ensure that the appropriate analyses are developed, evaluated, and chosen for implementation.

Coordinate the processing of particular data types with groups working with related data, both in the Project and outside of it.

Monitor those data types during the production of the full-scale dataset.

Work with the DCC and other databases to ensure that data processing pipelines function properly, and make modifications as needed.

Ensure that the data produced as part of this project, as well as any resource datasets produced as part of developing the methods for data analysis, are released to the Project DCC by procedures developed by the Steering Committee and the Analysis Group.

nsure that software developed as part of this project is made freely available to the broad research community.

Adhere to the NHGRI policies regarding intellectual property and other policies that might be established during the course of this activity.

Submit periodic progress reports in a standard format, as agreed upon by the Steering Committee and the Analysis Group.

Accept and implement the common guidelines and procedures approved by the Steering Committee and Analysis Group.

Accept and participate in the cooperative nature of the group.

Attend Steering Committee and Analysis Group calls and meetings, as appropriate.

Coordinate and collaborate with other U.S. and international groups working on the 1000 Genomes Project.

Awardees will retain custody of and
have primary rights to the data and software developed under these awards,
subject to Government rights of access consistent with current HHS, PHS, and
NIH policies.

2.
A.2. NIH Responsibilities

The NIH Program Director is a scientist
of the NHGRI extramural staff who will provide normal stewardship of the award
and, in addition, will have substantial scientific and programmatic involvement
during the conduct of this activity through technical assistance, advice, and
coordination. However, the role of NIH staff will be to facilitate and
not to direct the activities. It is anticipated that decisions in all
activities will be reached by consensus of the 1000 Genomes Steering Committee
and Analysis Group and that NIH staff will be given the opportunity to offer
input to this process. The NIH Program Director will participate as a
member of the Steering Committee and Analysis Group and will have one
vote. The NIH Program Director will have the following substantial
involvement:

Participate with the other Steering Committee and Analysis Group members in the group process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The NIH Program Director will assist and facilitate the group process and not direct it.

Serve as a liaison, helping to coordinate activities among and for the awardees, including acting as a liaison to the NHGRI and the other Institutes and Centers of the NIH, and as an information resource about extramural genome research activities.

Attend all Steering Committee and Analysis Group meetings as a voting member and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action. The NIH Program Director will be responsible for scheduling the time and preparing concise summaries of the Steering Committee and Analysis Group meetings

Report periodically on the progress of the 1000 Genomes Project to the Directors of the NHGRI and other NIH Institutes and Centers.

erve on subcommittees of the Steering Committee and the Analysis Group, as appropriate.

Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action.

Provide advice in the management and technical performance of the investigation.

Assist in promoting the availability of the 1000 Genomes and related resources developed in the course of this project to the scientific community at large.

Retain the option to recommend the withholding or reduction of support from any analysis group funded under this FOA that substantially fails to achieve its goals, fails to remain state of the art in its capabilities, or fails to comply with the Terms and Conditions of the award.

Participate in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the 1000 Genomes Consortium.

2.A.3. Collaborative Responsibilities

The 1000 Genomes Steering Committee will continue to serve as the main governing board of the 1000 Genomes Consortium. It includes the co-chairs of the Project as well as the co-chairs of all the working groups, a representative from each sequencing center, and some additional members, including the NHGRI Program Director. Almost all calls of the Steering Committee are open to all Project participants. The 1000 Genomes Analysis Group includes all the participants in the Project working on data processing and analyses, as well as the NIH Program Director. The P.I. from an awarded cooperative agreement as well as his/her relevant staff may be added to the Analysis Group, depending on the needs of the Project; any awardee groups not part of the Analysis Group would still be expected to work closely with the Analysis Group. The Steering Committee and Analysis Group may add additional members. Other government staff may attend the Steering Committee and Analysis Group calls and meetings if their expertise is required for specific discussions.

To
address particular issues, the Steering Committee and Analysis Group may
establish groups as needed, which would include representatives from the
grantees and the funding agencies, and possibly other experts. Each awardee P.I. will have one vote on the Analysis
Group. Awardees will be required to accept and implement the
common guidelines, procedures, and policies approved
by the Steering Committee and the Analysis Group.

2.A.4. Arbitration Process

Any disagreements that
may arise in scientific or programmatic matters (within the scope of the award)
between award recipients and the NIH may be brought to arbitration. An
Arbitration Panel composed of three members will be convened. It will have
three members: a designee of the Steering Committee chosen without NIH staff
voting, one NIH designee, and a third designee with expertise in the relevant
area who is chosen by the other two; in the case of individual disagreement,
the first member may be chosen by the individual awardee. This special
arbitration procedure in no way affects the awardee's right to appeal an
adverse action that is otherwise appealable in accordance with PHS regulations
42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to report progress on
a regular basis to the Analysis Group, in a way that the Analysis Group decides
on.

A
final progress report, invention statement, and Financial Status Report are
required when an award is relinquished when a recipient changes institutions or
when an award is terminated.

Section
VII. Agency Contacts

We
encourage your inquiries concerning this funding opportunity and welcome the
opportunity to answer questions from potential applicants. Inquiries may fall
into three areas: scientific/research, peer review, and financial or grants
management issues:

Human Subjects Protection:Federal
regulations (45CFR46) require that applications and proposals involving human
subjects must be evaluated with reference to the risks to the subjects, the
adequacy of protection against these risks, the potential benefits of the
research to the subjects and others, and the importance of the knowledge gained
or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and
Safety Monitoring Plan:Data and safety
monitoring is required for all types of clinical trials, including physiologic
toxicity and dose-finding studies (phase I); efficacy studies (Phase II);
efficacy, effectiveness and comparative trials (Phase III). Monitoring should
be commensurate with risk. The establishment of data and safety monitoring
boards (DSMBs) is required for multi-site clinical trials involving
interventions that entail potential risks to the participants (NIH Policy for
Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:Investigators
submitting an NIH application seeking $500,000 or more in direct costs in any
single year are expected to include a plan for data sharing or state why this
is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators
should seek guidance from their institutions, on issues related to
institutional policies and local IRB rules, as well as local, State and Federal
laws and regulations, including the Privacy Rule. Reviewers will consider the
data sharing plan but will not factor the plan into the determination of the
scientific merit or the priority score.

Policy
for Genome-Wide Association Studies (GWAS):NIH is interested in advancing genome-wide association
studies (GWAS) to identify common genetic factors that influence health and
disease through a centralized GWAS data repository. For the purposes of this
policy, a genome-wide association study is defined as any study of genetic
variation across the entire human genome that is designed to identify genetic
associations with observable traits (such as blood pressure or weight), or the
presence or absence of a disease or condition. All applications, regardless of
the amount requested, proposing a genome-wide association study are expected to
provide a plan for submission of GWAS data to the NIH-designated GWAS data
repository, or provide an appropriate explanation why submission to the
repository is not possible. Data repository management (submission and access)
is governed by the Policy for Sharing of Data Obtained in NIH Supported or
Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088.
For additional information, see http://grants.nih.gov/grants/gwas/

Access
to Research Data through the Freedom of Information Act:The Office of
Management and Budget (OMB) Circular A-110 has been revised to provide access
to research data through the Freedom of Information Act (FOIA) under some
circumstances. Data that are (1) first produced in a project that is supported
in whole or in part with Federal funds and (2) cited publicly and officially by
a Federal agency in support of an action that has the force and effect of law
(i.e., a regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has provided
guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this funding opportunity in a
public archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the application.
In addition, applicants should think about how to structure informed consent
statements and other human subjects procedures given the potential for wider
use of data collected under this award.

Sharing of Model
Organisms:NIH is committed to
support efforts that encourage sharing of important research resources
including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm).
At the same time the NIH recognizes the rights of grantees and contractors to
elect and retain title to subject inventions developed with Federal funding
pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm).
All investigators submitting an NIH application or contract proposal, beginning
with the October 1, 2004 receipt date, are expected to include in the
application/proposal a description of a specific plan for sharing and
distributing unique model organism research resources generated using NIH
funding or state why such sharing is restricted or not possible. This will
permit other researchers to benefit from the resources developed with public
funding. The inclusion of a model organism sharing plan is not subject to a
cost threshold in any year and is expected to be included in all applications
where the development of model organisms is anticipated.

Inclusion of Women
And Minorities in Clinical Research:It is the policy of the
NIH that women and members of minority groups and their sub-populations must be
included in all NIH-supported clinical research projects unless a clear and
compelling justification is provided indicating that inclusion is inappropriate
with respect to the health of the subjects or the purpose of the research. This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43). All investigators proposing clinical research should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new OMB
standards; clarification of language governing NIH-defined Phase III clinical
trials consistent with the new PHS Form 398; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a) all
applications or proposals and/or protocols must provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable; and b)
investigators must report annual accrual and progress in conducting analyses,
as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of
Children as Participants in Clinical Research:The NIH maintains a
policy that children (i.e., individuals under the age of 21) must be included
in all clinical research, conducted or supported by the NIH, unless there are
scientific and ethical reasons not to include them.

Required
Education on the Protection of Human Subject Participants:NIH policy
requires education on the protection of human subject participants for all
investigators submitting NIH applications for research involving human subjects
and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human
Embryonic Stem Cells (hESC):Criteria for
federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.
Only research using hESC lines that are registered in the NIH Human Embryonic
Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility
of the applicant to provide in the project description and elsewhere in the
application as appropriate, the official NIH identifier(s) for the hESC line(s)
to be used in the proposed research. Applications that do not provide this
information will be returned without review.

NIH Public Access Policy Requirement:In
accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html)
investigators must submit or have submitted for them their final, peer-reviewed
manuscripts that arise from NIH funds and are accepted for publication as of
April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly
available no later than 12 months after publication. As of May 27, 2008,
investigators must include the PubMed Central reference number when citing an
article in NIH applications, proposals, and progress reports that fall under
the policy, and was authored or co-authored by the investigator or arose from
the investigator’s NIH award. For more information, see the Public
Access webpage at http://publicaccess.nih.gov/.

Standards
for Privacy of Individually Identifiable Health Information:The Department
of Health and Human Services (DHHS) issued final modification to the
"Standards for Privacy of Individually Identifiable Health
Information", the "Privacy Rule", on August 14, 2002. The
Privacy Rule is a federal regulation under the Health Insurance Portability and
Accountability Act (HIPAA) of 1996 that governs the protection of individually
identifiable health information, and is administered and enforced by the DHHS
Office for Civil Rights (OCR).

Decisions about applicability and implementation of
the Privacy Rule reside with the researcher and his/her institution. The OCR
website (http://www.hhs.gov/ocr/)
provides information on the Privacy Rule, including a complete Regulation Text
and a set of decision tools on "Am I a covered entity?" Information
on the impact of the HIPAA Privacy Rule on NIH processes involving the review,
funding, and progress monitoring of grants, cooperative agreements, and
research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH
Grant Applications or Appendices:
All
applications and proposals for NIH funding must be self-contained within
specified page limitations. For publications listed in the appendix and/or
Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide
any other information necessary for the review because reviewers are
under no obligation to view the Internet sites. Furthermore, we caution
reviewers that their anonymity may be compromised when they directly access an
Internet site.

Healthy
People 2010:The Public
Health Service (PHS) is committed to achieving the health promotion and disease
prevention objectives of "Healthy People 2010," a PHS-led national
activity for setting priority areas. This FOA is related to one or more of the
priority areas. Potential applicants may obtain a copy of "Healthy People
2010" at http://www.health.gov/healthypeople.

Authority and
Regulations:This
program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive
Order 12372. Awards are made under the authorization of Sections 301 and 405 of
the Public Health Service Act as amended (42 USC 241 and 284) and under Federal
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the
terms and conditions, cost principles, and other considerations described in
the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly
encourages all grant recipients to provide a smoke-free workplace and
discourage the use of all tobacco products. In addition, Public Law 103-227,
the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in
some cases, any portion of a facility) in which regular or routine education,
library, day care, health care, or early childhood development services are
provided to children. This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

Loan
Repayment Programs:NIH encourages
applications for educational loan repayment from qualified health professionals
who have made a commitment to pursue a research career involving clinical,
pediatric, contraception, infertility, and health disparities related areas.
The LRP is an important component of NIH's efforts to recruit and retain the
next generation of researchers by providing the means for developing a research
career unfettered by the burden of student loan debt. Note that an NIH grant is
not required for eligibility and concurrent career award and LRP applications
are encouraged. The periods of career award and LRP award may overlap providing
the LRP recipient with the required commitment of time and effort, as LRP
awardees must commit at least 50% of their time (at least 20 hours per week
based on a 40 hour week) for two years to the research. For further
information, please see: http://www.lrp.nih.gov.